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WO2019073435A1 - Combinaisons d'inhibiteurs de mdm2 avec des inhibiteurs d'erk pour traiter des cancers - Google Patents

Combinaisons d'inhibiteurs de mdm2 avec des inhibiteurs d'erk pour traiter des cancers Download PDF

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Publication number
WO2019073435A1
WO2019073435A1 PCT/IB2018/057894 IB2018057894W WO2019073435A1 WO 2019073435 A1 WO2019073435 A1 WO 2019073435A1 IB 2018057894 W IB2018057894 W IB 2018057894W WO 2019073435 A1 WO2019073435 A1 WO 2019073435A1
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Prior art keywords
fluoro
inhibitor
mdm2
pharmaceutically acceptable
erk
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PCT/IB2018/057894
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English (en)
Inventor
Giordano Caponigro
Ensar HALILOVIC
Kelli-Ann Monaco
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Novartis AG
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Novartis AG
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Priority to JP2020520070A priority Critical patent/JP7332589B2/ja
Priority to US16/754,539 priority patent/US11406627B2/en
Priority to CN201880064287.0A priority patent/CN111163781B/zh
Priority to EP18797111.4A priority patent/EP3694518A1/fr
Publication of WO2019073435A1 publication Critical patent/WO2019073435A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical combination comprising an MDM2 inhibitor and an ERK inhibitor, for use in the treatment of a cancer, particularly in cancers having a mutation in the KRAS pathway.
  • the invention also relates to uses of these compounds in combination for the treatment of such cancers and for preparation of a medicament for the treatment of a cancer; methods of treating a cancer in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; pharmaceutical compositions comprising such
  • Mouse double minute 2 homolog (MDM2), also known as E3 ubiquitin protein ligase Mdm2, is a negative regulator of tumor protein p3 (p53). Binding of MDM2 to p53 promotes degradation of p53, which is a key regulatory mechanism keeping levels of p53 low in healthy, unstressed cells.
  • the protein p53 has numerous functions in cells, including that of tumor suppressor. In normal, unstressed cells, levels of p53 are low, but if the level of p53 increases, it can become activated and cause a number of cellular changes. In stressed or damaged cells, p53 increases and gets activated by
  • activated p53 can limit damage to the cell, such as by triggering DNA repair, or it can induce apoptosis, resulting in elimination of the damaged cell.
  • Inhibitors of MDM2 are compounds that interfere with binding of MDM2 with p53. Since disruption of the interaction of MDM2 with p53 leads to build-up of p53, and high levels of p53 can cause various effects including cell death, inhibitors of MDM2 can potentially stop tumor growth and even kill tumor cells. Indeed, at least seven inhibitors of MDM2 had entered clinical trials for treating various cancers by 2015. Zhao, et al., J. Med. Chem. 58(3), 1038-52 (2015).
  • Tumors with mutations in p53 may be less sensitive to MDM2 inhibitors if the mutations reduce the ability of the MDM2 inhibitor to disrupt binding of MDM2 to the mutated p53.
  • MDM2 inhibitors and ERK inhibitors demonstrate useful anticancer activity as separate monotherapies. Surprisingly, it has now been found that using an MDM2 inhibitor in combination with an ERK inhibitor can provide synergistic anticancer activity as demonstrated in xenograft models.
  • the invention provides a pharmaceutical combination comprising
  • an ERK inhibitor selected from 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)-2-fluorobenzamide ("Compound B” or "COMPOUND B”); 4-(3- amino-6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluoro-N-((S)-l-(3- fluoro-5-iodophenyl)-2-hydroxyethyl)benzamide; and (S)-4-(5-chloro-2- (isopropylamino)pyridin-4-yl)-N-(l-(3
  • Compound A (also referred to herein as "COMPOUND A”) is also known by the alternative name of (S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydro-pyridin-3-yl)-6-(4- chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-l-isopropyl-5,6-dihydro-lH- pyrrolo[3,4-d]imidazol-4-one.
  • a preferred ERK inhibitor for use in the combinations and methods of the invention is Compound B (also referred to herein as "COMPOUND B") which is 4-(3- amino-6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5- fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide:
  • This compound is an inhibitor of ERK 1 and ERK 2.
  • the compound is disclosed and its preparation described in published PCT patent application WO2015/066188. In some embodiments, this compound is used as its hydrochloride salt.
  • Another preferred ERK inhibitor for use in the methods and compositions of the invention is 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluoro-N- ((S)-l-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)benzamide:
  • This compound is an inhibitor of ERK 1 and ERK 2.
  • the compound is disclosed and its preparation described in published PCT patent application WO2015/066188.
  • ERK inhibitor that can be used in the methods of the invention is BVD-523, also known as ulixertinib, which is (S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(l-(3- chlorophenyl)-2-hydroxyethyl)-lH-pyrrole-2-carboxamide:
  • a pharmaceutical combination comprising:
  • an MDM2 inhibitor which is (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan- 2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and
  • an ERK inhibitor which is 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.
  • an MDM2 inhibitor which is (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)- 6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, for use in treating cancer in combination with an ERK inhibitor selected from 4-(3-amino- 6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5- fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide; 4-(3-amino-6-((l S,3S,4S)-3- fluoro-4-hydroxycycl
  • an ERK inhibitor selected from 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2-
  • an MDM2 inhibitor which is (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2- yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, for use in treating cancer by co-administration with an ERK inhibitor selected from 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3- bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide; 4-(3-amino-6- ((l S,3S,4S)-3-fluoro-4
  • an ERK inhibitor selected from 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)-2-fluorobenzamide;
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the pharmaceutical combination of the invention and at least one
  • the present invention relates to the pharmaceutical combination or the pharmaceutical composition of the invention for use as a medicine.
  • the present invention relates to the pharmaceutical combination or the pharmaceutical composition of the invention for use in the treatment of cancer.
  • the invention provides the use of to the pharmaceutical combination of the invention for the preparation of a medicament for the treatment of a cancer.
  • the present invention relates to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the present invention, or the pharmaceutical composition of the present invention.
  • the present invention provides the following aspects and specific
  • Cancers to be treated by the combination of the invention are listed below.
  • the combinations of this invention are particularly useful for treatment of subjects having cancer, e.g. melanoma, that comprises at least one KRAS mutation and/or at least one BRAF mutation.
  • FIGURE 1 In vitro results showing cell growth inhibition activity of combinations of (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one (Compound A) and 4-(3-amino-6-((l S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2- yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound B).
  • FIGURE 2A Patient Derived Xenograft (PDX) model from a BRAF-V600E patient relapsed on vemurafenib (Progression Free Survival (PFS) 46 weeks, best response stable disease) that had an additional activating MEK mutation, TP53 WT, and a biomarker signature indicating sensitivity to p53 re-activation.
  • CGM097 is (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4- methyl-3-oxo-piperazin-l-yl)4rans-cyclohexylmethyl]-amino ⁇ -phenyl)-l,4-dihydro-2H- isoquinolin-3-one.
  • FIGURE 2B Single mouse growth curves of the BVD-523 + CGM097 treated group highlighting the heterogeneity of response in PDX models. While the majority of tumors showed stable disease, two mice had early relapse and two mice had complete responses (CR). Dosing was stopped on day 38 for the whole group and the two CR mice showed regrowth of residual disease.
  • the present invention relates to a pharmaceutical combination comprising an MDM2 inhibitor used in combination with an ERK inhibitor, where the two compounds can be administered separately, sequentially or together, including as a single pharmaceutical composition. It provides methods for treating cancers using an MDM2 inhibitor in combination with an ERK inhibitor, and provides specific MDM2 and ERK inhibitors for use in these combinations and methods.
  • the combinations of the invention can be used to efficiently treat cancers.
  • the combination can be used to treat cancer due to a synergistic effect in inhibition of cell proliferation and / or induction of apoptosis that results from use in combination of the MDM2 inhibitor and the ERK inhibitor.
  • the invention allows use of a lower dosage of one or both compounds being administered to a subject treated with the combinations of the invention, or it produces a greater therapeutic benefit than would have been expected based on effectiveness of the separate compounds.
  • synergistic effect refers to action of two therapeutic agents such as, for example, at least one MDM2 inhibitor compound of the present invention and at least one ERK inhibitor compound of the present invention, producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch.
  • concentration-effect curve concentration-effect curve
  • isobologram curve concentration-effect curve
  • combination index curve concentration-effect curve
  • MDM2 inhibitor or “HDM2 inhibitor” or “Mdm2 inhibitor” as used herein, refer to any compound inhibiting the HDM2/p53 (Mdm2/p53) interaction association.
  • HDM2 Human homolog of murine double minute 2 is a negative regulator of p53.
  • Mdm2 inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of Mdm2/p53 association is indicated, e.g., in the treatment of tumors and/or cancerous cell growth.
  • Mdm2 inhibitors are useful in the treatment of human cancer, since the progression of these cancers may be at least partially dependent upon overriding the "gatekeeper" function of p53, for example the overexpression of Mdm2.
  • the Mdm2 inhibitor is the compound (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2- (2,4-dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol- 4(lH)-one, or a pharmaceutically acceptable salt thereof.
  • the MDM2 inhibitor is also referred to herein as Compound A.
  • This Mdm2 inhibitor belongs to a novel class of imidazopyrrolidinone compounds, and shows potent inhibition of the MDM2/p53 interaction (this term including in particular Hdm2/p53 interaction). In particular, this compound acts as an inhibitor of MDM2 interaction with p53 by binding to MDM2.
  • the invention encompasses succinic acid co-crystal of the (6S)-5-(5- Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one compound.
  • the compound can be also be in a form of an ethanol solvate.
  • CGM097 is an MDM2 inhibitor and is (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6- methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans-cyclohexylmethyl]- amino ⁇ -phenyl)-l,4-dihydro-2H-isoquinolin-3-one and is described in Example 106 of WO201 1/076786
  • WO2012/066095 describe the bisuphate salt and crystalline forms thereof.
  • the ERK inhibitor for use in the compositions and methods of the invention is prepared for administration via oral delivery, and may be used as its hydrochloride salt.
  • the compound or its HC1 salt is simply encapsulated in a pharmaceutically acceptable container such as a hard or soft gelcap for oral administration.
  • the gelcaps can be produced in a variety of dosages for flexible administration; for example, gelcaps can be prepared containing about 5 mg, about 20 mg, about 50 mg, or about 100 mg of Compound B or its HC1 salt.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable.
  • the compound may be capable of forming acid addition salts by virtue of the presence of an amino group.
  • reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • combination or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners to show a cooperative, e.g. synergistic effect.
  • the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially.
  • the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination.
  • fixed combination means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.
  • non-fixed combination means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.
  • the pharmaceutical combinations can further comprise at least one
  • the present invention relates to a
  • composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human.
  • the present pharmaceutical combinations can be formulated in a suitable pharmaceutical composition for enteral or parenteral
  • administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • the pharmaceutical combinations of the present invention can be used to manufacture a medicine.
  • the present invention relates to such pharmaceutical combinations or
  • compositions that are particularly useful as a medicine.
  • the combinations or compositions of the present invention can be applied in the treatment of cancer.
  • the present invention also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present invention for the preparation of a medicament for the treatment of a cancer, and to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present invention, or the pharmaceutical composition according to the present invention.
  • treatment comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human.
  • treatment comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells.
  • a "subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets.
  • a therapeutically effective amount of a compound (e.g. chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
  • the amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.
  • Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • a therapeutic amount or a dose of (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2- yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one may range between 100 and 1500 mg every three weeks, particularly between 100 and 800 mg every three weeks, or between 50 and 600 mg daily, when administered per os.
  • a therapeutic amount or a dose of (6S)- 5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one can be 400 mg, more preferably is 300 mg for daily administration for the first 21 days of every 28 day cycle.
  • a total therapeutic amount or a total dose of (6S)-5-(5- Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one is 560 mg per cycle (40 mg qd 2 wks on / 2 wks off, or 80 mg qd 1 wk on / 3 wks off).
  • the dosage for use in the combinations of the invention will typically be lower than those above, which are appropriate for use of this compound as a single agent.
  • a dosage between 100 and 500 mg every three weeks may be suitable, or a dosage of 50 to 400 mg daily may be suitable for oral administration, and lower dosages such as 200 mg or 300 mg daily for the first 21 days of a 28-day cycle may be used. Intravenous doses would need to be lowered accordingly.
  • each therapeutic agent may be conveniently administered, for example, in one individual dosage unit or divided into multiple dosage units. It is further understood that that each therapeutic agent may be conveniently administered in doses once daily or doses up to four times a day.
  • cancer is used herein to mean a broad spectrum of tumors, in particular solid tumors.
  • tumors include, but are not limited to a benign or malignant tumor of the lung (including small cell lung cancer and non-small-cell lung cancer), bronchus, prostate, breast (including sporadic breast cancers and sufferers of Cowden disease), pancreas, gastrointestinal tract, colon, rectum, colon carcinoma, colorectal cancer, thyroid, liver, biliary tract, intrahepatic bile duct, hepatocellular, adrenal gland, stomach, gastric, glioma, glioblastoma, endometrial, kidney, renal pelvis, bladder, uterus, cervix, vagina, ovary, multiple myeloma, esophagus, neck or head, brain, oral cavity and pharynx, larynx, small intestine, a melanoma, villous colon adenoma, a sarcoma,
  • the cancer is melanoma, liposarcoma, glioblastoma, neuroblastoma, colorectal cancer, lymphoma or leukemia.
  • the cancer is melanoma.
  • the present invention relates to melanoma having a mutation that confers resistance to a RAF inhibitor, such as V600E mutation of BRAF.
  • the melanoma is further characterized by a wild-type p53.
  • the combination is expected to achieve superior effects in functional p53 or p53 wild-type cancers.
  • the TP53 gene is one of the most frequently mutated genes in human cancers.
  • tumor suppressor p53 is functionally impaired by mutation or deletion in nearly 50% of human cancers.
  • p53 retains wild-type status but its function is inhibited by its primary cellular inhibitor, the murine double minute 2 (Mdm2, MDM2; HDM2 (human homolog of murine double minute 2)).
  • Mdm2 is a negative regulator of the p53 tumor suppressor.
  • Mdm2 protein functions both as an E3 ubiquitin ligase, that leads to proteasomal degradation of p53, and an inhibitor of p53 transcriptional activation. Often Mdm2 is found amplified in p53 wild-type tumors.
  • the combination of the present invention comprising the MDM2 inhibitor is particularly useful for treatment of functional p53 or p53 wild-type cancers.
  • the efficacy of the combination is expected to be increased in cancer, which is characterized by one or more of RAS or KRAS mutation and/or BRAF mutation.
  • Patients with melanoma harboring KRAS or BRAF mutations are generally associated with a poor prognosis (Arrington, Heinrich et al. 2012, Safaee Ardekani, Jafarnejad et al. 2012).
  • the combinations of this invention are particularly useful for treatment of subjects having melanoma that comprises at least one KRAS mutation and/or at least one BRAF mutation.
  • BRAF mutations include, but not limited to V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V. Most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.
  • V600E mutation has been detected in a variety of cancers, and is due to a substitution of thymine with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E).
  • the combinations of the invention may be useful in treating BRAF mutant melanoma, e.g. BRAF-V600E mutant melanoma. These melanoma may also be resistant to vemurafenib.
  • Example 1 illustrates synergy in vitro
  • Example 2 illustrates synergy in an in vivo xenograft model using a different combination of inhibitors of ERK and MDM2.
  • Example 1 The in vitro effects of combining the Mdm2 inhibitor COMPOUND A with the ERK inhibitor COMPOUND B on proliferation in melanoma cell lines WM-266-4 and A-375.
  • Cell lines were purchased from the American Type Culture Collection. A-375 cells were cultured in Dulbecco's Modified Eagle Medium (Life Technologies, Catalog #11995-065) and WM-266-4 cells were cultured in Minimum Essential Medium Alpha (Life Technologies, Catalog #12561-056). Both lines were supplemented with 10% FBS (Seradigm, Catalog #1500-500). All cell lines were determined to be free of mycoplasma contamination by a PCR detection assay performed at Idexx Radii (Columbia, MO, USA) and authenticated by SNP analysis. Cells were thawed from frozen stocks, expanded through >1 passage and grown at 37°C in 5% CO2.
  • cells were added to 96-well plates (Corning Costar, Catalog #3904) at a final volume of 80 ⁇ ⁇ per well and at density of 2500 cells (for A- 375) or 4000 cells (for WM-266-4) per well. After plating for 12-24 hours, 10 ⁇ . of each compound dilution series was transferred to plates in triplicate, resulting in the compound concentration ranges specified above. Additionally a day zero plate was assayed at this time using the CellTiter-Glo® Luminescent Cell Viability Assay, as described below. After 72 hours of compound treatment, the effects of compounds on cell proliferation were determined using the CellTiter-GloTM Luminescent Cell Viability Assay (Promega, Catalog #G7573).
  • the percent growth inhibition, excess inhibition and growth inhibition were calculated using Combo Module software using the Loewe synergy model (as described in Lehar et al. 2009), which measures the effect on growth above what would be expected if two drugs behaved in a dose additive manner. Positive numbers represent areas of increasing synergy.
  • the percentage of growth inhibition relative to DMSO is displayed in the panel labelled “Inhibition.”
  • the amount of inhibition in excess of the expected amount is in the panel labelled "ADD Excess Inhibition.”
  • the amount of inhibition normalized to day zero is displayed in the panel labelled "Growth Inhibition.”
  • EXAMPLE 2 Activity in Xenografts of a BRAF inhibitor-resistant melanoma.
  • the xenograft tissue was determined to have a BRAF V600E mutation and wild type p53, and also an additional unidentified activating MEK mutation.
  • a biomarker signature suggested the tissue would be sensitive to p53 re-activation. As expected, mice with this xenograft did not respond to a BRAF inhibitor.
  • mice having this xenograft were treated with CGM097 (100 mg/kg once per day by oral gavage), or BVD-523 (50 mg/kg twice daily by oral gavage), or both together (10 animals per treatment).
  • Figure 2A shows averaged tumor growth curves for each treatment. Rate of tumor growth in animals receiving the single-agent treatments did not differ much from controls. However, the combination of CGM097 plus BVD-523 largely stopped tumor growth over a period of 38 days. Thus treatment with BVD-523 and CGM097 together produced synergistic effects, resulting in stable disease over this period.
  • Figure 2B shows tumor growth curves for each individual animal in the combination treatment group. Two of the animals did not respond well to the combination treatment, but 6 exhibited stable disease out to 38 days, and two others exhibited marked tumor shrinkage, so 8 of 10 animals responded to the combination. Treatment was stopped at day 38 (arrow in Figure 2B), and tumor regrowth occurred in both of the animals whose tumors had nearly disappeared during treatment.

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Abstract

La présente invention concerne une combinaison pharmaceutique comprenant (a) un inhibiteur de MDM2 et (b) un inhibiteur d'ERK, destinée à être utilisée dans le traitement d'un cancer. Cette invention concerne également des utilisations de cette combinaison pour la préparation d'un médicament destiné au traitement d'un cancer; des méthodes de traitement d'un cancer chez un sujet nécessitant un traitement, comprenant l'administration audit sujet d'une quantité conjointement thérapeutiquement efficace de ladite combinaison; des compositions pharmaceutiques comprenant cette combinaison; et des kits et/ou des conditionnements contenant de telles combinaisons.
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